Hot flushes (or hot flashes or night sweats) are intermittent episodes of sweating and heat sensation associated with deficient circulating sex steroid levels. Hot flushes are experienced by 70-80% of all menopausal women, so affect millions of postmenopausal women worldwide each year, and they can negatively impact on quality of life (Carpenter, J. S., et al. Oncol. Nurs. Forum. 2002. 29(3):16-25; Hunter M., et al. Climacteric. 2010. 14(1):146-151; Archer D. F., et al. Climacteric. 2011. 14(5):515-528; and Thornton J. G., BMJ. 2012. 344). Hot flushes are also experienced by many patients undergoing treatment for cancer, for example patients receiving a breast or prostate cancer treatment which inhibits secretion of oestrogen or testosterone, respectively. Hot flushes induced by medical treatment can be referred to as “iatrogenic hot flushes”. Hot flushes are a common and important problem.
Hot flushes arise secondary to deficient circulating sex steroid levels. The exact cause of hot flushes is not well understood.
There are several known treatments for hot flushes. However, current treatments are not completely effective and may confer increased risk of serious complications. Hormone replacement therapy can alleviate hot flushes, but can lead to an increased risk of breast cancer, blood clots and pulmonary embolism (Ruddy K J, Partridge A H. J Clin Oncol. 2012. 30(30): 3705-3711). Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), gabapentin and clonidine may also be used for the treatment of hot flushes, but are not always effective at treating symptoms. Hot flushing is without adequate treatment options in clinical practice and therefore represents a substantial health burden without satisfactory therapeutic options.
Neurokinin B (NKB) is a member of the tachykinin family of peptides, which share a common C-terminal amino acid motif (Phe-X-Gly-Leu-Met-NH2) (Maggio J. E. et al. Annu Rev Neurosci 1988. 11:13-28). The other members of the tachykinin family of peptides are substance P and neurokinin A. There are three known tachykinin receptors: neurokinin-1 receptor (NKR1), neurokinin-2 receptor (NKR2) and neurokinin-3 receptor (NKR3). In humans, NKB is encoded by the TAC3 gene and binds preferentially to the neurokinin 3 receptor (Page N. M., Peptides. 2005 26(8): 1356-1368). Substance P and neurokinin A bind preferentially to the neurokinin 1 receptor and neurokinin 2 receptor, respectively.
WO 2003/037334 (Merck & Co. Inc.) describes the use of neurokinin-1 receptor antagonists for the treatment of hot flushes. The treatments described therein have not, as far as the current inventors are aware, been progressed in the clinic. It has been found by Mittelman-Smith M. A., et al that in rats with ovariectomy (surgical removal of the ovaries), ablation of NKB neurones using NK3-saporin prevented an increase in tail skin temperature and decrease in core body temperature, suggesting that NKB-expressing neurons are involved in vasoactive changes observed in ovariectomised rodents (Mittelman-Smith M. A., et al. Proc Natl Acad Sci USA. 2012. 27/109(48): 19846-51). Nakamura et al. and Yoshida et al have reported that the hypothalamic median preoptic nucleus MnPO, which receives information from warm-sensitive, cutaneous thermoreceptors and projects to CNS centres to modulate heat dissipation effectors, is a tissue that expresses the neurokinin 3 receptor (Nakamura K., et al Proc Natl Acad Sci USA. 2010. 107(19): 8848-8853; Yoshida K., et al. J Neurosci. 2009. 29(38):11954-11964). It has been found that C-fos expression (a marker of neuronal activation) in the MnPO is increased in ovariectomised rats when compared with ovariectomised and oestrogen-replaced rats. It was also reported that pharmacological activation of the MnPO by a selective NK3R agonist (senktide) reduced core temperature in ovariectomised rats (Dacks P. A., et al. Endocrinology 2011. 152(12):4894-4905). However, there remains considerable uncertainty about the role of NKR3 in human subjects, and its relevance as a target for treating human diseases.